1. Field of the Invention
The present invention relates to combinations of biomarkers that may be used, for example, in the prognosis or determination of future risk associated with the occurrence of a major adverse cardiac event (MACE) in a patient over a particular period of time.
2. Background Information
The ability to predict the risk of future major adverse cardiac events in patients presenting with signs and symptoms of acute coronary syndrome (ACS) is a significant achievement. Major adverse cardiac event (MACE) typically refers to the endpoints of death (either all cause or cardiac related), myocardial infarction (MI) and revascularization (either percutaneous coronary revascularization or coronary artery bypass surgery). Secondary endpoints often include congestive/chronic heart failure (CHF), stroke, re-revascularization and hospitalization for ACS or life threatening dysrythmias. In particular, with early determination of risk level, patients having a significant risk of such events can lower this risk by obtaining appropriate therapeutic intervention whether through surgery, administration of medications, changes in diet and exercise and/or periodic cardiac monitoring.
Acute coronary syndrome covers a group of clinical symptoms compatible with acute myocardial ischemia which is chest pain due to insufficient blood supply to the heart. In particular, it covers a spectrum of clinical conditions ranging from unstable angina to non-ST elevation myocardial infarction and ST-elevation myocardial infarction. The Redefinition of myocardial infarction in 2000 (J Am Coll Cardiol. 2000; 36:959-969) and the new Universal Definition of myocardial infarction in 2007 (Thygesen et al., J Am Coll Cardiol. 2007; 50:2173-95) established troponin as the definitive biomarker for the diagnosis of myocardial infarction along with clinical symptoms. Troponin was identified as the preferred marker, replacing CK-MB. Troponin I and T were first identified as serum markers of myocardial injury in the late 1970's (Clin. Sci. 1979; 56:30) and assays were described in the late 1980's (Am Heart J. 1987; 113:1333-44 and J. Mol. Cell. Cardiol. 1989; 21:1349-1353).
Troponin is a complex of three troponin molecules (i.e., Troponin I, Troponin T and Troponin C). Troponin T binds the troponin complex to tropomyosin, troponin I modulates the interaction of actin and myosin as an inhibitor of the actomyosin adenosine triphosphatase activity and troponin C is the calcium binding unit. The troponin complex is found in all striated muscle tissue including both skeletal and cardiac muscle. Troponin C exists in only one form in all types of striated muscle; on the other hand, troponin I and troponin T are found in three isoforms specific for cardiac, fast and slow muscle. The cardiac specific forms of Troponin I and Troponin T are the forms used for diagnosis of myocardial infarction. (The cardiac forms are denoted by a lower case c before the name, i.e., cTnI and cTnT.) cTnI and cTnT are released from the heart upon cardiac cell necrosis. Small cytosolic pools of Tn are known to exist and are released prior to further breakdown of muscle cells. The original literature describes the release of troponin as starting some 4-6 hours post injury (Wu et al., Clin Chem. 1999; 45:1104-21) and peaking at 12-16 hours; however, with newer, more sensitive assays, it appears that troponin is released much earlier, perhaps as soon as myoglobin.
The troponins circulate in the blood in several different forms. The exact circulating forms are not fully characterized, but it appears that the majority of the circulating cTnI is in a binary complex with TnC (Katrukha et al., Clin Chem. 1997; 43:1379-85), followed by the ternary complex of cTnI-TnC-cTnT, with very little free cTnI circulating. In addition, cTnI can be phosphorylated, reduced/oxidized and bound to heparin.
Previous studies have demonstrated the utility of single markers to risk stratify patients near term (i.e., 30 to 42 days) or mid term (i.e., 6 months) post initial presentation to the hospital. Ohman et al. and Antman et al. (NEJM 1996; 325:1331-41 and 1342-9) demonstrated the utility of troponin for near-term risk stratification. A substudy of the Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIa) investigated the potential of cardiac Troponin T (cTnT) to risk stratify patients with acute myocardial ischemia. Mortality within 30 days was significantly higher in patients with elevated cTnT levels. In the TIMI (Thrombolysis in Myocardial Infarction) IIIB trial, samples from patients with Acute Coronary Syndrome were analyzed for cardiac Troponin I (cTnI) and the relation between the level of cTnI and mortality at 42 days was determined There was a statistically significant increase in mortality with increasing levels of cTnI.
In another study, the ability of B-Type Natriuretic peptide (BNP) to predict risk in patients with unstable angina and non-ST-elevation myocardial infarction was evaluated (Morrow et al., J Am Coll Cardiol. 2003; 41:1264-72). Samples from patients enrolled in the TACTICS-TIMI (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy. Thrombolysis in Myocardial Infarction) 18 trial were evaluated. The ability to use BNP for risk assessment and clinical decision making over a range of cut points, alone and with cTnI in patients with non-ST-elevation acute coronary syndrome (ACS), was evaluated. Events were evaluated at seven days and six months. Patients with elevated BNP (>80 pg/mL) were at higher risk of death at seven days and 6 months, and this association was independent of cTnI. Patients with elevated BNP were also at higher risk for development of congestive heart failure (CHF) at 30 days. The authors concluded that elevated BNP at presentation identified patients with non-ST-elevation ACS who were at higher risk of death and CHF and adds incremental information to cTnI.
In addition to single markers, panels of biomarkers have been evaluated for their ability to risk stratify patients with acute coronary syndrome. Individual markers, as mentioned above, have been shown to predict adverse cardiac events. The utility of markers in combination to predict adverse cardiac events was evaluated using sample from patients enrolled in the OPUS-TIMI (Orbofiban in Patients with Unstable coronary Syndromes-Thrombolysis in Myocardial Infarction) study (Sabatine et al., Circulation. 2002; 105:1760-3). Baseline measurements of cTnI, CRP (c-Reactive protein) and BNP were measured. Elevations in cTnI, CRP and BNP each were independent predictors of death, myocardial infarction, or congestive heart failure. Categorizing the patients on the basis of number of elevated markers was associated with a near doubling of mortality risk for each additional positive marker. Similar relationships were also shown for the endpoints of MI, CHF and the composite at both 30 days and through 10 months.
A similar study utilizing the samples from patients in TACTICS-TIMI investigated a different panel of markers (Morrow et al. Eur. Heart J. 2008; 29:1096-1102). The prognostic utility of myeloperoxidase (MPO), soluble CD40 ligand (sCD40L), BNP, high sensitivity CRP (hsCRP) and cTnI for non-fatal recurrent ischemic events in non-ST-elevation ACS was investigated. Elevated baseline MPO was indicative of higher risk of non-fatal myocardial infarction or rehospitalization for ACS at 30 days. Stratification using baseline MPO, BNP and cTnI identified a >3-fold risk at 30 days for recurrent ischemic events. sCD40L was not associated with increased risk in this population.
In view of the above, there is a tremendous need for a significant and accurate predictor of major adverse cardiac events such that intervention can occur prior to the event of cardiac damage, damage that may be irreversible or even fatal. More specifically, biomarkers and the use thereof, as described herein, offer the ability to predict such events and thus allow physicians and patients the opportunity to implement the appropriate steps in order to save lives which would otherwise be lost without such prognostic information.
All patents and publications referred to herein are hereby incorporated in their entirety by reference.